X-152197701-A-G

Variant names:

• chrX-152197701-A-G
• NM_000808.4:c.863T>C

Variant summary

Our verdict is Uncertain significance. Variant got 4 ACMG points: 4P and 0B. PM2 PP3_Moderate

The NM_000808.4(GABRA3):​c.863T>C​(p.Met288Thr) variant causes a missense change involving the alteration of a conserved nucleotide. The variant was absent in control chromosomes in GnomAD project. In-silico tool predicts a pathogenic outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★).

• Frequency: Genomes: not found (cov: 23)
• Consequence: GABRA3 NM_000808.4 missense
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: 9.27

Genes affected

GABRA3 (HGNC:4077): (gamma-aminobutyric acid type A receptor subunit alpha3) GABA is the major inhibitory neurotransmitter in the mammalian brain where it acts at GABA-A receptors, which are ligand-gated chloride channels. Chloride conductance of these channels can be modulated by agents such as benzodiazepines that bind to the GABA-A receptor. At least 16 distinct subunits of GABA-A receptors have been identified. [provided by RefSeq, Jul 2008]

ACMG classification

Verdict is Uncertain_significance. Variant got 4 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• PP3: MetaRNN computational evidence supports a deleterious effect, 0.912

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
GABRA3	NM_000808.4	c.863T>C	p.Met288Thr	missense_variant	Exon 8 of 10	ENST00000370314.9	NP_000799.1
GABRA3	XM_006724811.4	c.863T>C	p.Met288Thr	missense_variant	Exon 8 of 9		XP_006724874.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
GABRA3	ENST00000370314.9	c.863T>C	p.Met288Thr	missense_variant	Exon 8 of 10	1	NM_000808.4	ENSP00000359337.4
GABRA3	ENST00000535043.1	c.863T>C	p.Met288Thr	missense_variant	Exon 8 of 10	1		ENSP00000443527.1

Frequencies

GnomAD3 genomes Cov.: 23

GnomAD4 exome Cov.: 28

GnomAD4 genome Cov.: 23

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:1

Revision: criteria provided, single submitter

Submissions by phenotype

Inborn genetic diseases Uncertain:1

Mar 15, 2022

Ambry Genetics

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

The c.863T>C (p.M288T) alteration is located in exon 8 (coding exon 7) of the GABRA3 gene. This alteration results from a T to C substitution at nucleotide position 863, causing the methionine (M) at amino acid position 288 to be replaced by a threonine (T). This variant was not reported in population-based cohorts in the Genome Aggregation Database (gnomAD). This amino acid position is highly conserved in available vertebrate species. This missense alteration is located in a region that has a low rate of benign missense variation (Lek, 2016; Firth, 2009). This alteration is predicted to be deleterious by in silico analysis. Based on insufficient or conflicting evidence, the clinical significance of this alteration remains unclear. -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Pathogenic	0.99
BayesDel_addAF	Pathogenic	0.43	D
BayesDel_noAF	Pathogenic	0.38
CADD	Pathogenic	26
DANN	Uncertain	0.99
DEOGEN2	Pathogenic	0.87	D;D
FATHMM_MKL	Pathogenic	0.98	D
LIST_S2	Uncertain	0.94	.;D
M_CAP	Pathogenic	0.54	D
MetaRNN	Pathogenic	0.91	D;D
MetaSVM	Uncertain	0.36	D
MutationAssessor	Uncertain	2.7	M;M
PrimateAI	Pathogenic	0.95	D
PROVEAN	Pathogenic	-4.6	D;D
REVEL	Pathogenic	0.89
Sift	Uncertain	0.0090	D;D
Sift4G	Pathogenic	0.0010	D;D
Polyphen		0.97	D;D
Vest4		0.80
MutPred		0.68		Gain of catalytic residue at M288 (P = 0.0061);Gain of catalytic residue at M288 (P = 0.0061);
MVP		0.91
MPC		2.8
ClinPred		0.99	D
GERP RS		5.0
Varity_R		0.80
gMVP		0.99

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.0		Details are displayed if max score is > 0.2

Find out detailed SpliceAI scores and Pangolin per-transcript scores at spliceailookup.broadinstitute.org

Publications

No publications associated with this variant yet.

Other links and lift over

hg19: chrX-151366173;